The goal of our proposal is to determine the role of the master regulatory cytokine, Interleukin 10 (IL10), in regulating proteostasis in mouse models of Alzheimer?s disease (AD) in an Apolipoprotein E (ApoE) isoform dependent manner. Our proposal addresses two key questions that are relevant to understanding of AD pathogenesis: (1) how does immune pathways interact with and modulate the function of AD risk genes, such as APOE and (2) can we harness this knowledge to disrupt the IL-10/APOE axis and achieve therapeutic benefits in AD-relevant mouse models? Our preliminary data has shown that the anti-inflammatory cytokine Interleukin (IL)-10, has unexpected negative effect on A? and tau proteostasis in transgenic mouse models of AD. This demonstrates a complex interplay between innate immunity and proteostasis in AD type neurodegenerative diseases, an interaction we call immunoproteostasis. The mechanism(s) underlying such immunoproteostasis leading to neurodegenerative pathology in AD remain unknown; studying the mechanisms underlying immunoproteostasis can enable us to design immunobiotherapies targeting such signaling pathways. We have observed that overexpression of IL-10 in APP transgenic mice worsens A? plaque pathology and cognitive functions via an ApoE-dependent mechanism. Mechanistically, we could attribute the negative effects of IL-10 on A? proteostasis to synergistic effects of decreased A? phagocytosis by microglia, increased endogenous ApoE expression and enhanced accumulation of ApoE in insoluble amyloid plaques. In our study, the increased level of insoluble ApoE was plaque-associated, consistent with mouse ApoE functioning as a pathological chaperone for A? aggregates. Blocking IL-10 signaling using the soluble decoy receptor against IL-10 abrogated this effect and reduced brain amyloid plaque burden. We observed similar ApoE dependent effects on tau proteostasis following IL-10 overexpression in two independent mouse models of tauopathy. Essentially, IL-10 accelerated tauopathy and reduced time to survival in JNPL3 mice; it also promoted forebrain neurodegeneration and tauopathy in the rTg4510 mice. While this was an unexpected phenotype, we provide preliminary data that ApoE specifically interacts with fibrillar tau in a cell free system, which could partially explain the proteostasis, though other mechanisms, such as autophagy inhibition also need to be considered. Guided by these robust preliminary data, we will undertake the following specific aims:
Aim 1. Assess whether APOE genotype affects IL10-induced proteostasis in APP mice and evaluate whether interaction of human APOE isoforms with A? aggregates alters microglial clearance of insoluble A?. We will test the effects of IL- 10 immunoproteostasis on amyloid plaque deposition in an APP transgenic mouse expressing human APOE protein (2 or 3 or 4) and provide mechanistic insights into APOE-dependent microglial uptake and clearance of aggregated A?. We expect that promoting expression of the protective APOE2 isoform will have beneficial effects while APOE4 induction will have harmful effects.
Aim2. Determine the effects of an AAV-delivered soluble IL-10 receptor decoy (sIL10R1) strategy in APP, tau and non- transgenic mice. Given that IL-10 worsens proteostasis and AD-relevant phenotype in mouse models of A? and tau, herein, we will test the efficacy of a decoy receptor strategy against IL-10. By blocking IL-10 signaling, we expect the decoy receptor strategy to be a potentially translatable disease modifying therapy against both A? and tau proteostasis.
Aim3. Replicate and extend our studies of IL-10 overexpression as a driver of tau pathology. Herein, using the AAV toolkit, and systems biology approach, we propose to reproduce our observations of IL-10/APOE-dependent proteostasis phenotype in a well-controlled and behaviorally-characterized tau transgenic cohort and further provide insights into possible mechanisms underlying such amyloidogenic properties of the IL-10/APOE axis. The strength of this proposal lies in the teamwork between a new investigator with continuing commitment to studying the neuroimmune axis in mouse models of AD and an established investigator with experience in creating transgenic AD mouse models. We expect that this proposal will enhance our knowledge of the complex immune signaling cascades in AD proteostasis and uncover translatable immune decoy receptor strategies targeting APOE-regulated proteostasis.
Innate immunity plays a key role in Alzheimer?s disease (AD) pathogenesis, though the underlying mechanisms are unclear. We have previously reported that an anti-inflammatory cytokine, Interleukin (IL)-10 worsens Alzheimer-type pathology and cognition in amyloid ? mouse model of AD through an Apolipoprotein E (ApoE) dependent mechanism. In parallel, we have conducted experiments in mouse models of Alzheimer-like tau pathology and uncovered evidence that IL-10 expression similarly induces ApoE protein and accelerates tauopathy. This project investigates the mechanisms underlying how IL-10 alters Alzheimer-like pathology and cognition in amyloid ? and tau mouse models by regulating the foremost genetic risk factor for AD - ApoE- and further focuses on assessing decoy immune receptor strategies as therapies against the IL-10/ApoE axis.
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